Indocyanine Green | Chemical Properties, Uses and Side ...

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Indocyanine Green | Chemical Properties, Uses and Side Effects
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What is Indocyanine Green

Indocyanine green or Indocarbocyanine is a nontoxic, fluorescent tricarbocyanine dye used in medical diagnostics. It is used to measure cardiac output (heart function) and liver blood flow. In medical procedures such as angiography, it can also be used to make certain parts of the eye more visible.

Besides uses in cancer treatment, indocyanine green injections are used to identify or detect problems with liver blood flow, tissue perfusion, and blood vessels before, during, or after surgery or to diagnose or find problems with lymph nodes in the cervix, or to diagnose or treat lymphomatous diseases of women with uterus or cervix tumours.

Chemical properties

• Indocyanine Green is a tricarbocyanine dye with a molecular formula C43H47N2NaO6S2 and a molecular weight of 775 daltons.
• It occurs as a dark green to blue-green solid, while its solution is deep emerald-green in colour.
• The chemical name for Indocyanine Green is 1-H-Benz[e]indolium or 2-[7-dihydro-1,1-dimethyl-3-(4-sulfobutyl)-2H-benz[e]indol-2-ylidene]-1,3,5-Heptatrienyl]-1,1-dimethyl-3-(4-sulfobutyl)-, hydroxide, inner salt, sodium salt.
• It is generally odourless or has a slight odour.
• It absorbs best at 800 nm.
• Indocyanine Green solubility &#; It is soluble in water and in methanol but practically insoluble in most other organic solvents.
• It decomposes gradually above 200 °C.
• The pH of ICG for Injection USP is 6.5 when reconstituted.

Optical Properties

Indocyanine green (ICG) is a negatively charged, water-soluble tricarbocyanine dye whose absorption and fluorescence spectra are dependent on the concentration and on the solvent utilized. ICG&#;s absorption and fluorescence spectra are in the near infrared (NIR) range. It absorbs mainly between 600 nm and 900 nm (mainly around 780 nm) and emits fluorescence between 750 nm and 950 nm. Since the fluorescence spectrum is so broad (max. values ranging to 810 nm in water and approx. 830 nm in blood) , the substantial overlap between the absorption and fluorescence spectra results in a significant reabsorption of fluorescence by ICG itself.

How does Indocyanine Green work

ICG is a nontoxic dye, which is exclusively metabolized by the liver in humans. Following an intravenous infusion at a rate ( R ) below the metabolic capacity of the liver, a steady state is reached within 1 h. ICG levels are then measured in the hepatic vein (HV) and peripheral blood. As ICG is not metabolized anywhere else, the ICG concentration in peripheral blood is equivalent to that in the hepatic artery (HA) or the portal vein (PV). Therefore, hepatic blood flow can be calculated by the Fick principle: Flow = R /(ICG Peripheral &#; ICG HV ).

Also, ICG  has the property of fluoresces, i.e. emits light, after excitation under near-infrared light at 806&#;nm light. ICG is highly soluble in water and binds to β-lipoproteins, particularly to albumin. Because of the high protein content of lymph, ICG accumulates in the lymphatic pathways and lymph nodes. ICG-dyed lymph nodes become visible 5 minutes after light excitation and remain visible for around 60 minutes. Thus, Indocyanine Green is used in Fluorescence Imaging with Near-Infrared Light to Identify Sentinel Lymph Nodes, Lymphatic Vessels and Pathways Prior to Surgery.

Uses of Indocyanine green

Indocyanine green (ICG), the only FDA-approved cyanine dye, has been used for decades as a non-targeting contrast agent for optical imaging in opthalmic angiography. Besides this, it is a prescription medicine used as a diagnostic agent for determining Cardiac Output, Hepatic Function and Liver blood flow. The various applications of Indocyanine green are discussed below in detail.

 Indocyanine green angiography

Indocyanine Green Angiography (ICGA) is a diagnostic procedure that uses ICG dye to examine the blood flow in the CHOROID &#; the layer of blood vessels which lies underneath the retina. The choroid is the layer of blood vessels and connective tissue between the sclera (white of the eye) and retina. It supplies nutrients to the inner parts of the eye.

The procedure is similar to fluorescein angiography. Indocyanine Green dye is injected into a vein in the arm/hand. Each vial of Indocyanine Green for Injection USP comprises 25 mg of Indocyanine Green as a sterile lyophilized powder containing less than 5% sodium iodide. As the dye passes through the blood vessels of your eye, photographs are taken to record the blood flow. The Indocyanine Green dye is generally tolerated without any problems. The most common application of indocyanine green angiography is the detection of choroidal neovascularization, a common component of age-related macular degeneration. Refer here to know more.

Capsulorhexis

Capsulorhexis is performed through cataract surgery to remove the lens capsule. The lens capsule is stained with various dyes during the procedure. Horiguchi et al. described the first use of indocyanine green dye for staining capsular tissue in . During childhood cataract surgery, ICG-enhanced anterior and posterior capsulorhexis can be beneficial. Adult cataracts without fundus glow might also benefit from ICG-enhanced capsulorhexis. US FDA has approved ICG, but no approval has been given for intraocular use.

Perfusion diagnostics of tissues and organs

Blood flow to tissues and organs can be assessed using this method in many medical fields. Using a camera attached directly to a near-infrared light source, the fluorescence can be excited. In real-time, ICG fluorescence can be viewed and documented with a digital video camera. In addition, ICG can also be used as a tracer in cerebral perfusion diagnostics. Fluorescence and ICG absorption measurements can be used in everyday clinical settings to monitor stroke patients during the recovery phase.

Indocyanine green lymphography

Indocyanine green (ICG) lymphography is an emerging imaging technique used to visualize lymphatic vessels and map their course as they drain to sentinel lymph nodes. ICG has become an alternate popular method for imaging lymphatics. ICG lymphography was initially used for breast sentinel node biopsy. Its application then extended to lymphoedema diagnosis and mapping of lymphatic vessels prior to lymphovenous anastomosis (LVA) surgery. Gastric cancer lymphatic drainage can also be visualized using indocyanine green (ICG) fluorescence lymphography.

Sentinel lymph node biopsy while undergoing tumour removal with ICG

It is a minimally invasive method of assessing whether malignant tumours have spread to local lymph nodes using a sensitized lymph node biopsy (SLN biopsy). In the first lymph node, the &#;sentinel&#;, there may be a tumour of the entire lymph node area that is draining and not present elsewhere. The ICG fluorescence navigation method is highly sensitive and offers high rates of detection. Even though the new method presents a difficult learning curve, it combines lymphography and SLB, making it possible to perform an SLB without the use of radioactive substances.

Selectively over-heating cells (especially cancer)

Indocyanine Green absorbs light at wavelengths of about 805 nanometers, along with other near-infrared wavelengths. Using an 800 nm to 810 nm laser, it is possible to heat or overheat ICG-injected tissue without damaging surrounding tissues. ICG kills cells primarily through overheating. Tumours naturally absorb more ICG than other tissues, so it works particularly well on cancer tumours.

Side Effects of Indocyanine Green

Medicine may also have some unwanted effects, in addition to its needed effects. It is possible that some of these side effects are not experienced, but if they do, medical treatment may be required.

• Cough
• Difficulty with swallowing
• Dizziness
• Excessive sweating
• Headache
• Fast heartbeat
• Hives or welts
• Itching or rash on the skin
• Swollen lips, face, or tongue
• Tightness in the chest
• Fatigue, or low energy

Other side effects not listed may also occur in some patients. If any of the following side effects occur, speak with your doctor or nurse as soon as possible.

Precautions while using Indocyanine green

• It is very important that your doctor checks your or your child&#;s progress to make sure this medicine is working properly and to check for unwanted effects.
• Anaphylactic reactions, such as anaphylaxis, can result from using ICG. Symptoms of ICG may include rashes, itching, swelling of your face, tongue, and throat, difficulty breathing or swallowing, and chest pain. Reach out to your doctor if you experience anything odd or out of the symptoms.
• Make sure any doctor or dentist who treats you knows that you are receiving this medicine. This medicine may affect the results of certain medical tests.
• Consult your doctor before taking any other medicines. Medications covered include prescriptions, over-the-counter (OTC) medications, herbal supplements, and vitamins.

FAQs

Where to buy Indocyanine green (ICG)?

Macsen Drugs, a unit of Macsen Labs, is one of the leading cGMP manufacturers and suppliers of Indocyanine green with WHO-GMP Certification and USFDA registration.

What is the difference between Fluorescein and Indocyanine Green angiography?

ICG dye has a high protein binding capacity (about 98%) and thus can image the choroidal vasculature better than fluorescein angiography. To know more in detail you may refer here.

How long does Indocyanine green stay in your system?

Indocyanine Green stays in the vessels for up to 30 minutes due to its binding to plasma proteins (intravenously). In an eye examination, blood stays for a long time in tissues with higher blood flow, like the choroid and the retinal blood vessels.

When do you give Indocyanine green?

PINPOINT Endoscopic Fluorescence Imaging System for laparoscopic cholecystectomy showed that the optimal timing of indocyanine green administration for fluorescent cholangiography was 15 hours before surgery.

How do you take Indocyanine green?

Indocyanine green is administered as a rapid IV bolus for hepatic function studies.

What is the half-life of ICG dye?

ICG has a half-life of between 150 and 180 seconds and is eliminated from circulation entirely by the liver through the production of bile juice.

Does Indocyanine green contain Iodine?

Yes, indocyanine green (ICG) contains iodine. Because of its iodine component, testing for iodine intolerance must be carried out before injecting the dye to prevent the risk of anaphylaxis or other allergic reactions. Indocyanine green is contraindicated in patients who are hypersensitive to iodine or other substances that contain iodine such as shellfish or X-Ray dye.

Is Indocyanine green Nephrotoxic?

ICG is non-nephrotoxic, excreted exclusively by the liver, with incidences of minor and major complications being exceedingly rare.

If you are looking for more details, kindly visit Laser Retinal Imaging.

Who manufactures ICG?

Macsen Labs is a GMP and ISO-certified manufacturer of high-quality indocyanine green.

Is Indocyanine green (ICG) a dark fluorophore?

Indocyanine Green is a fluorescent tricarbocyanine dye used in medical diagnostics. It absorbs mainly between 600 nm and 900 nm and emits fluorescence between 750 nm and 950 nm.

Is ICG FDA approved?

Indocyanine green is an FDA-approved dye.

What is Indocyanine Green made of?

Indocyanine Green Injection USP comprises 25 mg of Indocyanine Green as a sterile lyophilized powder containing less than 5% sodium iodide.

Who invented ICG?

In , the Kodak research laboratories created ICG dye for near-infrared (NIR) photography, and in , the FDA approved its clinical usage.

What is cholecystectomy with ICG?

Cholecystectomy with ICG involves its uses during laparoscopic cholecystectomy (gall bladder removal) for a better understanding of the anatomy of the biliary tree and to prevent or reduce the risk of bile duct injury.

What is the frequency at which ICG emits light?

ICG absorbs mainly between 600 nm and 900 nm and emits fluorescence between 750 nm and 950 nm.

Resources on Indocyanine Green

Indocyanine Green Injection for Angiography

Indocyanine Green | Uses in Medical Imaging & Surgery

Disclaimer-

The information provided here is based on general knowledge, articles, research publications etc and we do not claim the authenticity of any of the information provided above. We do not claim or suggest/advise any medical, therapeutic, health or nutritional benefits of Indocyanine green. We do not supply or promote our Indocyanine green product for the applications which are covered by valid patents and which are not approved by the FDA.

Macsen Labs is a manufacturer and supplier of high-quality Indocyanine Green.

Abstract

Introduction:

Postoperative wound complications after resection of soft-tissue sarcomas are challenging. Indocyanine green (ICG) angiography has previously been used to predict wound complications, but not for soft-tissue sarcomas. We aimed to evaluate whether this technology could help lower wound complications after soft-tissue sarcoma resections.

Materials and Methods:

We conducted a prospective study from 10/ to 9/ using ICG angiography during sarcoma resection surgery. Rates of wound complications were compared with a historical control consisting of surgeries before utilization of ICG angiography.

Results:

A total of 88 patients were included in the study. We found significantly lower rates of infection (11.8% versus 38%; P = 0.03) and wound dehiscence (11.8% versus 42.3%; P = 0.02) in the ICG angiography cohort compared with the historical controls.

Conclusion:

ICG angiography use during soft-tissue sarcoma resections is promising technology and warrants further investigation to help reduce postoperative complications.

Postoperative wound complications after resection of a soft-tissue sarcoma are a challenging issue. Historically, rates of wound complications after preoperative radiation therapy and surgical resection have been reported to be greater than 30%.1-3 Unfortunately, little progress has been made over time, with similar rates reported in more recent literature.4,5

Wound dehiscence and infection are the predominant causes of postoperative wound complications in these patients. Previous studies have reported on risk factors for developing these complications and include preoperative radiation, size of the tumor, location of the tumor, smoking status, diabetes, and vascular disease.3,4,5,6,7 A number of interventions such as more aggressive flap coverage, hyperbaric oxygen therapy, silver dressings, or wound vacuum technology have achieved some success in mitigating the wound complication risk in this population.7-9 However, there is still ample room to improve complication rates.

A previous limitation for surgeons treating sarcomas was the inability to predict the tissue's capacity to heal in real time, during the operative setting. Knowing the tissue at risk would allow the surgeon to change the reconstruction plan at the time of surgery to decrease the risk of developing postoperative wound complications. Indocyanine green (ICG) angiography provides the surgeon this ability and has successfully been used in plastic surgery, general surgery, and more recently in orthopaedic surgery, to predict the survival of tissue and planned flaps. 10,11,12,13 We recently reported on ICG angiography use in sarcoma surgery, demonstrating that it was predictive of developing a postoperative wound complication, especially in the lower extremity.14 What is unknown, however, is whether use of this technology will translate to lower postoperative wound complication rates.

We hypothesized that ICG angiography use would reduce postoperative wound complications, specifically wound dehiscence and infection, in soft-tissue sarcoma resections after preoperative radiation therapy. We conducted a prospective study using intraoperative ICG angiography and compared the wound complication rates with historical controls.

Methods

After institutional review board approval, a prospective study was conducted from 10/ to 9/ to evaluate the ability of intraoperative indocyanine green fluorescence angiography to reduce postoperative wound complications after soft-tissue sarcoma resection. Eligible patients included those with a diagnosis of a nonmetastatic soft-tissue sarcoma who were scheduled for elective surgical resection. Patients were then included in the study if ICG angiography was used to evaluate and manage their reconstruction. Exclusion criteria included patients with an iodine allergy who could not undergo ICG angiography due to cross-reactivity.

During the surgical procedure, the sarcoma resection was done routinely. The reconstruction was then done with the assistance of the microvascular team if a local flap or free flap was required. After wound closure, and before application of the dressing, the incision was evaluated using ICG fluorescence angiography. One vial of ICG powder (25 mg/vial) was reconstituted with 10 mL of sterile water to create a 2.5 mg/mL solution. Five milliliters of the solution was injected intravenously, followed by a 10-mL sterile saline flush. Images were then captured using the PDE-NEO II handheld device (Mitaka). Areas of hypoperfusion were marked with a surgical pen. These areas were then excised until the entire incision appeared well perfused, as evaluated with follow-up fluorescence angiography. Rates of wound dehiscence and infection were recorded. Dehiscence was defined as an unexpected separation of the tissue layers, whereas infection was defined as any patient requiring antibiotic therapy secondary to wound drainage or cellulitis. Patients were followed postoperatively until the incision had healed, and then every 4 months for surveillance imaging, per our institutional guidelines.

The prospective intraoperative angiography cohort was then compared with a cohort (control group) consisting of patients who underwent soft-tissue sarcoma resection before the institutional adoption of this technology for sarcoma patients. Chart review was done on these historical cohort patients, who underwent surgery from 1/ to 5/, to obtain patient demographics and surgical details.

Statistical Analysis

Patient demographics, tumor characteristics, and rates of complications were described and compared using the Fisher exact test for categorical variables. The Student t-test was used to compare means of continuous variables. A P value of less than 0.05 was considered significant. Statistical Package for the Social Sciences (SPSS), version 25, software (SPSS) was used for the analyses.

Results

Eighty-eight patients were included in the study. Seventeen patients (19%) underwent sarcoma resection with wound closure guided by intraoperative fluorescence angiography, whereas 71 patients (81%) served as historical controls.

In the intraoperative fluorescence angiography cohort, there were nine males (52.9%) and eight females (47.1%). The average age at the time of surgery was 58 years (range 29 to 86 years), whereas the average body mass index was 27 kg/m2 (range 20 to 36.8 kg/m2). Patient demographics compared with historical controls are listed in Table , with the only significant difference being a higher rate of peripheral vascular disease documented in the fluorescence angiography cohort.

Table 1

VariablesControlFluorescence Angiography P N = .0%N = .0%Age (mean ± SD)59.617.557.716.90.69Sex>0.99&#;Males.1%952.9%&#;Females.9%847.1%BMI, kg/m2 (mean ± SD)29.537.427.25.10.23Smoking0.62&#;No.9%.6%&#;Yes912.7%15.9%&#;Only history.4%423.5%Steroids use0.59&#;No.5%.1%&#;Yes68.5%15.9%Diabetes0.38&#;No.3%.1%&#;Yes912.7%15.9%PVD 0.04 &#;No.2%.4%&#;Yes22.8%317.6%CAD0.42&#;No.7%.5%&#;Yes.3%423.5%Open in a separate window

In the fluorescence angiography cohort, 15 patients (88.2%) underwent radiation, all of which was given preoperatively (neoadjuvant) per our institutional protocol. The average radiation dose was 50 Gy. In addition, five patients (29.4%) received chemotherapy; two received neoadjuvant therapy (11.8%), whereas three (17.6%) received adjuvant treatment. We found no differences in the rates of radiation or chemotherapy given between the angiography cohort and the historical controls (P > 0.05) (Table ).

Table 2

VariablesControlFluorescence Angiography P N = .0%N = .0%Tumor location0.44&#;Upper extremity.7%529.4%&#;Lower extremity.4%.6%&#;Thorax68.5%00.0%&#;Pelvis/genitalia68.5%00.0%Tumor size (cm)&#;Mean ± SD8.867.67.885.50.61Radiation therapy0.07&#;No.6%211.8%&#;Yes.4%.2%Chemotherapy0.62&#;No.4%.6%&#;Yes.6%529.4%Closure0.17&#;Primary.5%741.2%&#;Local flap.6%423.5%&#;Free flap79.9%211.8%&#;Skin graft45.6%317.6%&#;Free flap and skin graft11.4%00.0%&#;Local flap and skin graft00.0%15.9%Infection 0.03 &#;No.0%.2%&#;Yes.0%211.8%Wound dehiscence 0.02 &#;No.7%.2%&#;Yes.3%211.8%Open in a separate window

The average size of the tumors was 7.88 cm in the angiography cohort (range: 1 to 22 cm). Five tumors (29.4%) were located in the upper extremity, and 12 (70.6%) were found in the lower extremity. Six tumors (35%) were superficial to the fascia, and 11 tumors (65%) were deep. All 17 patients underwent resection with a wide margin. We found no differences in tumor characteristics between the prospective cohort and the historical controls (P > 0.05).

In the angiography cohort, seven wounds (41.2%) underwent primary closure. Four (23.5%) were closed with local flaps, whereas two (11.8%) required a free flap. Three patients (17.6%) underwent a split-thickness skin graft. Thirteen patients (77%) had an incisional wound vac placed at the time of wound closure. We found no differences in the types of closure between the cohorts (P > 0.05).

Intraoperative fluorescence angiography demonstrated that five patients (29.4%) had hypovascular areas of skin along their incision after wound closure (Figure ). All five of these patients had this skin excised during the procedure. Two of these patients (11.8%) developed a wound complication postoperatively; both complications were due to wound dehiscence. The remaining three patients (17.6%) did not develop a wound complication.

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There were an additional three patients (17.6%) who developed wound complications that were not predicted by intraoperative fluorescence angiography. All three of these patients had issues related to the partial breakdown of a split-thickness skin graft. Two of the patients (11.8%) developed a superficial infection; one required a return to the operating room for a débridement.

When comparing rates of postoperative infections in the fluorescence angiography group with our historical controls, we found a statistically significant lower rate of infections in the angiography cohort (11.8% versus 38%; P = 0.03). Similarly, rates of wound dehiscence were also significantly lower in the angiography cohort compared with the control group (11.8% versus 42.3%; P = 0.02).

Discussion

Wound complications after sarcoma resection are a challenging issue. Preoperative radiation is associated with a higher rate of developing these complications than with postoperative treatment. This was demonstrated by O'Sullivan et al5, who reported a 35% wound complication rate in their preoperative cohort, compared with 17% when patients received radiation therapy in the postoperative setting. Despite this, many clinicians, including our center, still choose preoperative radiation due to other advantages such as a smaller radiation field, lower radiation dose, and less long-term fibrosis.15

Clinicians have attempted to reduce the wound complication rate with preoperative radiation therapy to more similarly match the risk observed with postoperative treatment by identifying risk factors for developing complications as well as using techniques, such as hyperbaric oxygen or wound vacuum technology, to reduce the risk. So far, however, we have not seen a substantial decrease in wound complication rates.4,5 We think a major limitation has been the inability to directly visualize the vascular supply to the tissue intraoperatively, which would allow removal of tissue with poor perfusion and healing potential at the time of the index surgery.

ICG angiography is a technology that allows direct visualization of tissue perfusion intraoperatively. It distributes entirely in the intravascular space, allowing accurate visualization of tissue perfusion. In addition, it has a very short half-life (3 minutes), which is ideal if recurrent dosing is required.16,17 It has been shown to accurately detect perfusion abnormalities and reduce wound healing complications in a variety of procedures.13,17,18,19,20 For example, in a study by Rinker,10 skin-sparing mastectomies demonstrated decreased skin flap necrosis when evaluated intraoperatively with ICG compared with direct visualization of skin perfusion.

Before our institutional adoption of ICG angiography for soft-tissue sarcoma resections, we had an infection rate of 38% and a wound dehiscence rate of 42.3%, similar to complication rates reported in the literature associated with preoperative radiation.1-3,5 After including this technology in our surgical reconstruction plan, we have demonstrated a significant decrease in wound dehiscence rates and infections, more closely approximating complication rates observed with postoperative radiation therapy at 11.8% in our cohort.

There were three patients in our prospective cohort who developed partial breakdown of a split-thickness skin graft. None of these patients had hypoperfusion detected with the ICG angiography. Given that split-thickness skin grafts require more than just a well-vascularized tissue bed to heal, we do not think that ICG angiography is helpful in predicting success for split-thickness skin grafts.

There are several limitations to this study. Namely, we have a small sample size. Despite this, we were able to demonstrate a statistically significant difference in wound dehiscence and infection rates between the cohorts. In addition, the comparison group was retrospective in nature. A prospective randomized trial would be a higher level of evidence. Last, this study was conducted at a single institution. Larger, multi-institutional studies are needed to verify these results. Despite these limitations, we think that this study is important because it has shown a drastically reduced rate of wound complications when using intraoperative indocyanine angiography during sarcoma resection.

Conclusion

In conclusion, we found statistically significantly lower wound complication rates, specifically for infection and wound dehiscence, after sarcoma resections when using intraoperative ICG angiography. We recommend continued use of this technology.

Footnotes

Dr. Wilke or an immediate family member has received research or institutional support from Summit Medical and the Desmoid Research Foundation. Dr. Forte or an immediate family member has received research or institutional support from the Plastic Surgery Foundation. None of the following authors or any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Schultz, Dr. Huayllani, Dr. Boczar, Dr. Spaulding, Dr. Sherman, and Dr. Murray.